A multifaceted analysis of sensitivity factors in perinatal carcinogenesis is in progress. In a pharmacogenetic and pharmacokinetic study of transplacental carcinogenesis by methylcholanthrene (MC), genetic backcrosses were made to obtain, in the same mother, fetuses which were either inducible or noninducible for the enzymes which metabolize MC. The inducible fetuses from two dose groups exhibited a significantly higher incidence of lung tumors (two- to three-fold greater) than did those of the noninducible phenotype. This is the first direct demonstration of a determining role of enzyme inducibility in fetal susceptibility to a carcinogen. This finding will be confirmed and extended to other carcinogens and mouse strains and to noncarcinogenic enzyme inducers. Radioactive MC administered to pregnant mice attained high concentrations rapidly in the amniotic fluid and fetal blood and remained at high levels there, suggesting sequestration of the chemical in the fetal compartment. In an assay of the transplacental plus chronic lifetime exposure effects of the nitroso derivative of the drug cimetidine (nitrosocimetidine, NCM), no increase was seen in incidences of any neoplasm, but there was an apparent enhancement of lung tumor growth in females and lung tumor metastasis in males. This effect could be suggestive of either transplacental causation of lung tumors by NCM or direct effects on development of spontaneously-arising tumors. These possibilities will be tested in further studies in which NCM will be applied to lung and skin tumors initiated by other known carcinogens. New studies just starting include determination of promotion in suckling mice by polychlorinated biphenyls, and assessment of the transplacental neurogenic effects of nitrosamines in C3H mice, in an attempt to obtain an animal model for perinatal causation of brain tumors by nitrosamines.